Outcomes from conventional therapy of patients with oral cancer have not significantly improved in over 30 years. There are few therapeutic options for patients with recurrent and unresectable oral cancers. Our patients need novel therapies to improve outcomes. Herpes oncolytic viruses are a new class of agents that have demonstrated potent therapeutic effects in treating oral cancers in preclinical studies. These viruses have been attenuated for safe application, and have reached phase I clinical trials with encouraging results. Our group has repeatedly identified a remarkable ability by these viruses to specifically infect selected cancers while preserving normal tissues. The mechanisms for these observations are unknown. Although certain genetic deletions within our oncolytic viruses might promote preferential viral replication in tumor tissues, they do not account for observations of preferential viral binding, viral entry and immediate-early gene expression. Our preliminary studies have identified the differential expression of glycoprotein D (gD) HSV receptors by oral cancer cells as an important determinant of herpes oncolytic efficacy. One receptor, nectin-1, is particularly highly correlated with successful oncolytic HSV entry into target cancer cells and subsequent cell lysis. Nectin-1 also serves as an important component of intercellular adherens junctions (AJ's), which are critical in normal cell-cell interactions. AJ's are frequently dysregulated in oral cancers through the repression of E-cadherin by a process called epithelial-mesenchymal transition (EMT). EMT is an important event in cancer progression that dysregulates normal epithelial organization and promotes invasion and metastasis. Our preliminary data suggest that EMT may be directly linked to the liberation of nectin-1, increased nectin-1 availability, and natural susceptibility to oncolytic herpes viral therapy. We propose experiments designed to elucidate the relationships between EMT and the exposure of oral cancer cell surface nectin-1 as a functional receptor to herpes oncolytic therapy. These studies will: (1) examine the natural expression of herpes gD receptors and adherens junctions components on normal oral mucosa, dysplasia, and carcinomas, (2) study the effect of modulation EMT and E-cadherin on nectin-1 expression and its function as a herpes viral receptor, and (3) determine if such effects on nectin-1 and other HSV receptors may account for observations of differential targeting ability by these oncolytic herpes viruses in vivo. These studies have a potential to (1) link a fundamental process of cancer progression with natural susceptibility to therapeutic herpes vectors, (2) promote a novel concept of viral binding and entry (rather than viral replication) as an important determinant of oncolytic viral efficacy, and (3) elucidate novel tumor markers of herpes oncolytic susceptibility that can be used to select patients with oral cancers for enrollment in upcoming clinical trials with these promising biological agents. PUBLIC HEALTH RELEVANCE: Preclinical studies have suggested that many oral cancers are susceptible targets to herpes oncolytic viral therapy. This proposal explores the specific mechanisms by which oral cancer cells may naturally express higher levels of receptors to herpes envelope glycoproteins than normal cells, permitting more selective infection and destruction of oral cancer cells. The results from this proposal will (1) promote a new understanding of how herpes viruses target cancer cells, and (2) identify tumor markers that can be used to predict response to herpes oncolytic therapy, and that can be used to guide patient selection in upcoming clinical trials.